Methane → 2-(Difluoromethyl)-4-methoxy-1H-benzimidazole

HRID 1256439Notes

Reaction equation

HRID 1256439 reaction equation
[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[F:13][CH:14]([F:18])[C:15](O)=O.Cl.C>[Pd].CO.O>[NH3:1].[F:13][CH:14]([F:18])[C:15]1[NH:10][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[N:1]=1

Participants

9

Reactant 4

HCID 297MethaneHCID 313Hydrochloric AcidHCID 9788Difluoroacetic acidHCID 854916-Nitro-o-anisidine

Product 2

HCID 222AmmoniaHCID 534881012-(Difluoromethyl)-4-methoxy-1H-benzimidazoleYield 170.4%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 962WaterSolvent

Procedure

2-Amino-3-methoxynitrobenzene (15.10 g, 0.09 mol) was hydrogenated over palladium on carbon in methanol, and the solution was filtered through celite into a methanolic HCl solution. The solvent was removed under vacuum and the resulting hydrochloride salt was combined with difluoroacetic acid (19.2 g, 0.18 mol) and 4 M HCl (100 mL). The mixture was heated under reflux for 3 hrs, diluted with water, decolorized with charcoal, and filtered through celite. Neutralization with aqueous ammonia gave 2-difluoromethyl-4-methoxy-1H-benzimidazole (15.2 g, 84%) as a solid: 1H NMR (CDCl3) (tautomeric mixture) δ 9.95-9.70 (m, exchangeable with D2O, 1H), 7.44 (br d, J=7.9 Hz, 0.4H), 7.31-7.24 (m, 1H), 7.12 (br d, J=8.0 Hz, 0.5H), 6.89 (t, JHF=53.8 Hz, 1H), 6.82-6.74 (m, 1H), 4.03 and 3.98 (2s, 3H).

Workup

  1. filtrationthe solution was filtered through celite into a methanolic HCl solution
  2. customThe solvent was removed under vacuum
  3. temperatureThe mixture was heated
  4. temperatureunder reflux for 3 hrs
  5. filtrationfiltered through celite

Sources & evidence

ORD record
ord-2918dc6005c94ef8ba4b695d6140dba0
Source dataset
uspto-grants-2013_06
Patent number
US08461158B2

Reaction notes

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